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Lipid-like Self-Assembling Peptides
SHUGUANG ZHANG*
Laboratory of Molecular Design, Center for Bits and Atoms, Massachusetts
Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts
02139-4307, United States
RECEIVED ON JANUARY 30, 2012
CONSPECTUS
O
ne important question in prebiotic chemistry is the search for simple structures that
might have enclosed biological molecules in a cell-like space. Phospholipids, the
components of biological membranes, are highly complex. Instead, we looked for molecules
that might have been available on prebiotic Earth. Simple peptides with hydrophobic tails
and hydrophilic heads that are made up of merely a combination of these robust, abiotically
synthesized amino acids and could self-assemble into nanotubes or nanovesicles fulfilled our
initial requirements. These molecules could provide a primitive enclosure for the earliest
enzymes based on either RNA or peptides and other molecular structures with a variety of
functions.
We discovered and designed a class of these simple lipid-like peptides, which we describe in this Account. These peptides consist of natural amino acids (glycine, alanine, valine,
isoleucine, leucine, aspartic acid, glutamic acid, lysine, and arginine) and exhibit lipid-like
dynamic behaviors. These structures further undergo spontaneous assembly to form
ordered arrangements including micelles, nanovesicles, and nanotubes with visible openings. Because of their simplicity and
stability in water, such assemblies could provide examples of prebiotic molecular evolution that may predate the RNA world. These
short and simple peptides have the potential to self-organize to form simple enclosures that stabilize other fragile molecules, to
bring low concentration molecules into a local environment, and to enhance higher local concentration. As a result, these structures
plausibly could not only accelerate the dehydration process for new chemical bond formation but also facilitate further selforganization and prebiotic evolution in a dynamic manner.
We also expect that this class of lipid-like peptides will likely find a wide range of uses in the real world. Because of their
favorable interactions with lipids, these lipid-like peptides have been used to solubilize and stabilize membrane proteins, both for
scientific studies and for the fabrication of nanobiotechological devices. They can also increase the solubility of other waterinsoluble molecules and increase long-term stability of some water-soluble proteins. Likewise, because of their lipophilicity, these
structures can deliver molecular cargo, such as small molecules, siRNA, and DNA, in vivo for potential therapeutic applications.
Introduction
There was then much excitement about RNA since RNA
A Simple Question: What Is the Simplest Enclosure
System in Water in a Prebiotic Environment? In June
1992 at the “Origin of Life” Gordon Conference in New
was found to catalyze self-splicing and self-replicating and
Hampshire, almost all active players in the origin of life field
There was a sense of overturning the protein dominant
in the world gathered. The participants include scientists
from diverse fields: astronomy, atmospheric science, geol-
world, as it was called the RNA World.
I at the meeting openly asked two seemingly very simple
ogy, geochemistry, organic chemistry, biochemistry, and
questions that did not directly related to protein or RNA. The
molecular biology, as well as patent law. They included the
two questions were (1) what could be the simplest amphi-
legendary Stanly Miller and Leslie Orgel, as well as leading
philic biomolecules that could self-organize to enclose
figures Jack Szostak, Gerry Joyce, Christopher Chyba, James
€ nter von Kiedrowski, and Gunter
Brack, Gu
Ferris, Andre
other biological molecules in a primarily aqueous prebiotic
€chtersha
€user.
Wa
self-assembled from the simplest of amino acids?
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take part in a wide range of other biological actions that
were seemingly impossible to imagine even in early 1980s.
environment and (2) could such structures be made and
Published on the Web 06/21/2012 www.pubs.acs.org/accounts
10.1021/ar300034v
& 2012 American Chemical Society
Lipid-like Self-Assembling Peptides Zhang
FIGURE 1. The lipid-like peptides. These peptides have a hydrophilic
head and a hydrophobic tail, much like lipids or detergents. They
sequester their hydrophobic tail inside of micelles, vesicles, or nanotube
structures, and their hydrophilic heads are exposed to water. At least
three kinds molecules can be made, with , þ, or - heads and in two
orientations.
I reasoned that the prebiotic enclosure biopolymers could
neither be phospholipids nor nucleic acids because they are
relatively complex multicomponent molecules containing
several distinctive parts.1,2 Furthermore, it takes much chemical energy to make a lipid molecule with a long chain to
form reduced carbons. Similarly, nucleic acids are complex
molecules themselves and may not be able to form tight
enclosures, like a membrane system. Likewise, proteins as
we know them today seem to be unlikely actors in the
prebiotic environment because polymerization of any specific
sequence from a “soup” of possible monomers encounters
unavoidable problems of combinatorial mathematics. In short,
abiotic syntheses of all three types of complex molecules in the
prebiotic environment seem rather unlikely.
I therefore asked whether it was plausible that the simplest peptides with hydrophobic tails and hydrophilic heads
(Figure 1), comprising just two or three kinds of the simple
amino acids, as short as a few amino acids, could function in
this simplest enclosure-forming capacity. Although several
groups had studied the chemistry of various amino acids and
amino acid biopolymers,36 distinctive enclosure structures
were then not reported in the literature.
Simple Amino Acids and Their Condensation
under Prebiotic Conditions
Glycine (side chain R = H), alanine (R = CH3), and aspartic acid
(R = CH2COOH) are among the chemically and structurally
simplest amino acids. They are of particular interest to
prebiotic molecular evolution because of their presence
not only in the products of biochemical simulations of
Earth's presumed prebiotic environment,710 but also in
the CI-type carbonaceous chondrites, including Orgueil,
Ivuna, and Murchison meteorites.1115 Specifically, glycine
is the simplest possible amino acid, and it is an achiral
molecule without any true side chains and is presumed to
be the most abundant amino acid in abiotic environments.
Beyond synthesis of the amino acids themselves, it has
been experimentally demonstrated that amino acids and
their derivatives can form peptides when subjected to
repeated hydrationdehydration cycles under microwave
heating, in aqueous ammonia, or on heated clays that
mimic various hypothesized conditions of early life on the
planet.6,16,17 Indeed, oligoglycine appears to be produced
abiotically, as it has been synthesized by subjecting glycine
monomers to ∼40 h of supercritical water conditions at
270 °C and high-pressure at 10 MPa.18
These high-temperature and high-pressure conditions
are similar to those found in deep-sea volcanoes and hydrothermal vents, a favorite hypothesized venue for the origin
of life. It is plausible that some of the simplest biochemical
building blocks could have produced complex life forms
over eons of natural selection and evolution. The challenge,
however, is to explain how sufficiently complex proteins or
ribozymes could have been produced in the lipid membranes necessary for the metabolism of their own catalysis
and reproduction.
If, instead of lipid membranes, simple peptides with
hydrophobic tails and hydrophilic heads that are made up
of merely a combination of these robust, abiotically synthesized amino acids could self-assemble into nanotubes or
nanovesicles, they would have the potential to provide a
primitive enclosure for the earliest RNA-based19,20 or peptide enzymes and other molecular structures with a variety
of functions.
In other words, if such structures could be demonstrated
to exist, this would provide a plausible idea that in the
prebiotic world, these lipid-like peptides of various lengths
could form and self-organize into distinct vesicles and tubes,
which could act as naturally formed enclosures, isolated
from the environment, for prebiotic rudimentary enzymes
and ribozymes to accumulate. From this starting point, it is
far easier to envision how a diverse population of peptides
and RNA could not only condense into complex structures but also increasingly evolve into sophisticated systems, stimulate their own synthesis, and replicate and
evolve ultimately into the wondrously efficient chemical
and biological catalysts ubiquitous today.21,22
Lipid-like Peptides
A class of simple amphiphilic lipid-like peptides that consist
of plausible prebiotic amino acids was designed (Figure 2).
The first peptide, Ac-AAAAAAD-OH, was designed with
computer modeling, linking amino acids together one at a
time to achieve a similar length and shape to lipids. This class
of these molecules comprises peptides that exhibit lipid-like
or surfactant properties.2327
Not only do the shape and physical structure of these lipidlike peptides resemble lipids and other organic surfactants, but
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FIGURE 2. Molecular models of peptide detergents at neutral pH. (A) Molecular structures of individual glycine tail-based surfactant peptides: (a) G4D2,
(b) G6D2, (c) G8D2, and (d) G10D2. The tail length of glycines varies depending on the number of glycine residues. The lengths of these molecules in the
extended conformation range from 2.4 nm for G4D2 to 4.7 nm for G10D2. (B) Other amino acid-based tails: (a) Ac-AAAAAAD-COOH; (b) Ac-AAAAAAKCONH2; (c) DAAAAAA-CONH2; (d) KAAAAAA-CONH2; (e) Ac-VVVD-COOH; (f) Ac-VVVK-CONH2; (g) Ac-IIID-COOH; (h) Ac-IIIK-CONH2; (i) Ac-LLLD-COOH;
(j) Ac-LLLK-CONH2; (k) Ac-GAVILEE; (l) Ac-GAVILRR.43 Aspartic acid (D) is negatively charged, and lysine (K) is positively charged. The hydrophobic tails
of the peptide detergents consist of alanine (A), valine (V), isoleucine (I), and leucine (L). Each peptide is ∼22.5 nm long, similar in size to biological
phospholipids. Color code: teal, carbon; red, oxygen; blue, nitrogen; and white, hydrogen.
TABLE 1. A List of Ultrasmall Peptidesa
head group
heptamer
hexamer
pentamer
tetramer
trimer
aspartic acid (D)
glutamic acid (E)
lysine (K)
serine (S)
threonine (T)
LIVAGDD
LIVAGEE
LIVAGD*, ILVAGD*, LIVAAD, LAVAGD, AIVAGD*
LIVAGE *
LIVAGK
LIVAGS*, ILVAGS, AIVAGS
LIVAGT, AIVAGT
LIVAD, LIVGD
IVAD*, IIID
IVD, IID
IIIK
a
A group of 27 peptides that self-assembled to ordered supramolecular networks, resulting in hydrogel formation. All peptides were acetylated at the N-terminus,
while the carboxyl group at the C-terminus was unchanged, except for LIVAGK, which was amidated to suppress the charge at the C-terminus. The D-isoform of some
peptides (marked with *) were also studied. Peptides that were investigated more extensively are shown in bold, namely, LIVAGD (also named Ac-LD6), AIVAGD (also
named Ac-AD6), and IVD (also named Ac-ID3). From Hauser et al., 2011.28 Reprinted with permission from PNAS.
their chemical properties do as well. For example, peptides have
either six hydrophobic alanine or valine residues from the
N-terminus, followed by a negatively charged aspartic acid
residue (A6D = Ac-AAAAAAD; V6D Ac-VVVVVVD); they possess
two negative charges, one from the charged terminal side chain
and the other from the C terminus.23 In contrast, several simple
peptides, G4DD (Ac-GGGGDD), G6DD (Ac-GGGGGGDD), G8DD
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(Ac-GGGGGGGGDD), have four, six, or eight glycines, followed
by two asparatic acids with three negative charges.24 Similarly,
Ac-A6K (Ac-AAAAAAK-NH2) or KA6 (KAAAAAA-NH2) has six
alanines as the hydrophobic tail and a positively charged lysine
as the hydrophilic head.25
Charlotte A. E. Hauser designed a unique class of ultrasmall peptides as small as only three amino acids, Ac-IVD
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FIGURE 3. Molecular models of the ultrasmall self-assembling peptides
and dimensions. Schematic representation of the peptide motif
Ac-LIVAGD (Ac-LD6) and Ac-AIVAGD (Ac-AD6). From Mishra et al.29
Reprinted with permission from Elsevier.
and Ac-IID (∼1 nm), or four amino acids, Ac-IVAD, Ac-IIID and
Ac-IIIK (Table 1; Figure 3). These peptides readily undergo
self-assembly to form stable and well-ordered nanostructures.2830 Despite their small size, these peptides show a
secondary conformational transition from structurally unorganized monomers into metastable R-helical intermediates that terminate in cross-β structures. The peptides have a
characteristic sequence motif that consists of an aliphatic
amino acid tail of decreasing hydrophobicity capped by a
polar head, which makes them amphiphilic. The selfassembled nanostructures formed by this peptide class include
long helices, straight fibers, and hollow nanospheres that
could form the simplest enclosures in the prebiotic environment.2830 In some cases, these peptide form the shortest
helical structure and very stable and strong hydrogels.2830
Although individual chemical species within this population of
peptides have completely different composition and sequence,
they share a common feature: a hydrophilic head comprising one or two charged amino acids and a hydrophobic tail
comprising two or more consecutive hydrophobic amino acids
(Figure 3; Table 1). Furthermore, noncharged hydrophilic heads
using serine and threonine have also been made (Table 1), in
their possession of a hydrophobic tail and a hydrophilic head
without charges.2830
Self-Organized Nanotubes, Nanovesicles, and
Other Nanostructures
These lipid-like peptides self-organize in water to form wellordered nanostructures, which include micelles, nanotubes,
and nanovesicles (Figures 46). Furthermore, the structure formation is concentration-dependent, namely, at low
concentration, there are no defined structures, these structures spontaneously assemble at a critical aggregation concentration (CAC),2630 and they behave similarly to lipids
and other surfactants.
Five amino acids of varying hydrophobicity (Gly, Ala, Val,
Ile, and Leu) have been used for the nonpolar tails. Such
hydrophobic tails are two to six residues so that the total size
of the peptide detergents is between three and seven amino
acids, about 12.4 nm in length. Interestingly, 2.4 nm is a
similar size to that of the phospholipid, which is very
abundant in cell membranes. The common lipid bilayer
membrane is ∼5 nm, and the hydrophobic part is ∼4.8 nm.
The first lipid-like peptide was designed by modeling the
Ac-A6D-OH peptide using phosphatidylcholine as a size
guide. However, when peptides with more than six hydrophobic residues (except glycine) were synthesized, the peptides become less and less soluble in water. We used
aspartate (), glutamate (), and lysine (þ), arginine (þ),
and histidine (þ) as the hydrophilic head groups; they can
also be used in various combinatorial ways. Therefore, they
can broaden the range of fine variations and increase the
possible number of peptides.
Bucak and colleagues used small-angle X-ray scattering
and cryo-SEM image to study AAAAAAK and found that
above its critical concentration (CAC), A6K self-assembles
into several-micrometer-long hollow nanotubes with a
monodisperse cross-sectional radius of 26 nm. Because the
peptides carry a positive charge, the nanotubes are chargestabilized. Because of the very large aspect ratio, the tubes
form an ordered phase that presumably is nematic, suggesting the favorable self-assembly of antiparallel peptide dimers into β-sheet ribbons that wrap helically to form the
nanotube wall.31,32
Moreover, similar to the dynamic behavior of phospholipid
vesicles and other microstructures,33 these simplest of peptide
nanostructures appear to behave as dynamic entities in
water;they fuse, divide, and change shape as a function of
time and environmental influence (Figures 46).2330
Cones and Other Shapes of Peptides
It is known that lipids have different shapes depending on
their aliphatic chains, some with straight aliphatic chains and
some with bent shapes with unsaturated chains. These lipids
can make curvatures of a variety of cellular structures.
Inspired by natural lipid shapes, I also designed some
cone-shaped lipid-like peptides. For example, Ac-GAVILRRNH2 has a cone shape, with the largest part made of arginine
and smallest part glycine (Figure 7).34 Thus this peptide
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FIGURE 4. (A, B) High-resolution TEM images of G6D2 showing different structures and dynamic behaviors of these structures: (A) (a) A pair of fingerlike structures branching off from the stem. (b) Enlargement of the box in image a, the detail opening structures are clearly visible. (c) The openings
(arrows) from the nanotube which may have resulted in the growth of the finger-like structures. Some nanovesicles are also visible. (d) The
nanovesicles may undergo fission (arrows). (b) Nanotubes and nanovesicles of lipid-like peptide ac-VVVVVVD-OH in water. Micelles are also present.
Examples of vesicles budding off of a nanotube are included. Image courtesy of Dr. Steve Yang. (C) AFM image of nanotubes of A6K lipid-like selfassembling peptides. When the solution pH is less than the lysine pKa of 10, the peptide bears a positive charge. The openings of peptide nanotubes
are clearly visible. These nanotube structures can also undergo structural changes depending on various conditions, particularly pH changes, ionic
strength of salts, temperature, and incubation time. The other sheet-like materials are likely the unassembled peptides at the time of image collection.
formed a structure with curvature when it self-organized into
nanostructures in water. A donut-shaped structure has been
observed under AFM (Figure 8). Several cone-shaped peptides from Hauser's laboratory, such as Ac-LIVAGK-NH2,
Ac-LIVAGEE-OH, Ac-LIVAGD-OH, and Ac-AIVAGD-OH, selfassemble into nanospheres and other interesting nanostructures, thus further broadening the repertoire (Figure 3).2830
glutamic acid.2330,35 When the lipid-like peptides with
positively and negatively charged peptides are combined
together, they further interact to form some interesting
structures; however individually they do not form such
structures.36 The synergistic assembly is worth further study
since in nature, there are always molecular complexes and
multiple molecular interactions.
Synergistic Self-Assembly of Lipid-like
Peptides
Lipid-like Peptides Interact with Lipid and SDS
The lipid-like peptides have two different charges of head
groups, one positively charged with lysine and arginine or
histidine, the other negatively charged with aspartic acid or
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Since the lipids and the lipid-like peptides share many
common chemical and structural features, we asked
whether the lipid-like peptides interact with lipids. Experiments with monoolein showed close interactions of these
Lipid-like Self-Assembling Peptides Zhang
FIGURE 5. Quick-freeze/deep-etch TEM images of pSA6. Upper panels
show examples of several individual nanotubes. The nanotube openings are clearly visible. A magnified image shows the budding vesicles.
Lower panels give an overview of two different regions of the areas,
showing the presence of nanotube and nanovesicle structures. The
areas with many budding vesicles can be discerned.
peptides with monoolein.37 The ternary MO/peptide/water
system has been studied using small-angle X-ray scattering
(SAXS), within a certain range of peptide concentrations and
temperatures (2570 °C). We demonstrated that the bilayer
curvature and the stability are modulated by (i) the peptide/
lipid molar ratio, (ii) the peptide molecular structure, namely,
the degree of hydrophobicity, the type of the hydrophilic
amino acid, and the headgroup location, and (iii) the temperature. The anionic peptide surfactants, Ac-A6D and DA6,
exhibit the strongest surface activity.
At low peptide concentrations, the Pn3m structure is still
preserved, but its lattice increases due to the strong electrostatic repulsion between the negatively charged peptide
molecules, which are incorporated into the interface. This
means that the anionic peptides have the effect of enlarging
the water channels, and thus they serve to enhance the
accommodation of positively charged water-soluble active
molecules in the Pn3m phase.
At higher peptide concentration, the lipid bilayers are
destabilized, and the structural transition from the Pn3m to
the inverted hexagonal phase (H2) is induced. For the
cationic peptides, our study illustrates how even minor
modifications, such as changing the location of the headgroup (Ac-A6K vs KA6), significantly affects the peptide's
effectiveness.37 Only KA6 displays a propensity to promote
FIGURE 6. Filed emission scanning electron microscope (FESEM)
images of different structures formed from two ultrasmall self-assembling peptides: (A) Ac-AIVAGD-OH (5 mg/mL) and (B) Ac-LIVAGD-OH (0.1
mg/mL). From Mishra et al.29 Reprinted with permission from Elsevier.
FIGURE 7. Molecular models and self-assembled donut-shaped structure of Ac-GAVILRR-NH2. The peptide length is approximately 2.3 nm,
and the width is 1.2 nm. Color code: hydrogen = white, carbon = cyan,
oxygen = red, and nitrogen = blue. The cone-shaped model is simplified
for the shape of Ac-GAVILRR-NH2. The blue part indicates the positively
charged hydrophilic region, and the yellow part indicates the hydrophobic region.
the formation of hexagonal phase, which suggests that KA6
molecules have a higher degree of incorporation in the
interface than Ac-A6K.
Although as short as only seven residues, Ac-A6K formed
stable R-helical structures in sodium dodecyl sulfate (SDS).
These short R-helices are able to stabilize R-helical motifs,
which are commonly found in transmembrane domains of
diverse membrane proteins. Experiments also showed that
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FIGURE 8. AFM image of the donut structure of the self-assembled AcGAVILRR-NH2 is presented. (A) The AFM image of the aggregation
structures at 2 μM in water. The square enlarges one of the nanodonut
structures. (B) The dimensions of the donut structure.
Ac-A6D and Ac-A6K could form β-sheets and appear as
hydrogels at higher concentrations. Furthermore, Ac-A6D
and Ac-A6K together in SDS formed expected β-sheet structures via a surprising R-helical intermediate.36
Lipid-like Peptides Stabilize Membrane
Proteins
Since they behave like lipids and interact with monoolein
lipid and other surfactants, I asked that whether these
peptides could stabilize membrane proteins. Our studies
using these peptides showed that they indeed stabilized a
wide range of membrane proteins (Figure 9) including
Escherichia coli glycerol-3-phosphate dehydrogenase,38 the
multidomain protein complex photosystem-I (PSI) on a
surface in dry form39 and in aqueous solution,40 G-protein
coupled receptor (GPCR) bovine rhodopsin,41 and olfactory receptors.42,43 Furthermore, we have demonstrated
that these lipid-like peptides are excellent materials for
cell-free production of over 20 GPCRs with milligram
yields.42,43
The Lipid-like Peptides and Relevance to
Prebiotic Molecular Evolution
It is presumably plausible that in the prebiotic world, under
the influence of water, lipid-like peptides of various lengths
might self-organize into distinct vesicles and tubes regardless
of sequences that could enclose prebiotic rudimentary enzymes so as to isolate them from the environment. Thus, a
diverse population of peptides and RNA might condense into
complex structures that evolve to different functions.21,22
The existence of diverse and stable nanostructures demonstrates how biochemical molecular selections could
give rise to complex entities, presumably through a process
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FIGURE 9. A proposed scheme for how the designer lipid-like peptides
stabilize membrane proteins. These simple designer self-assembling
lipid-like peptides have been used to solubilize, stabilize, and crystallize
membrane proteins. These peptides have a hydrophilic head and a
hydrophobic tail, much like other biological lipids. They use their tail to
sequester the hydrophobic part of membrane proteins, and the hydrophilic heads exposed to water. Thus, they make membrane proteins
soluble and stable outside of their native cellular lipid milieu. These lipidlike peptides are very important for overcoming the barrier of high
resolutions of molecular structure for challenging membrane proteins.
of prebiotic molecular evolution applied to primitive, quasiliving autocatalytic networks.
When one considers prebiotic molecular selection and
evolution in the context of the origin of life, the enormously
powerful force of water must never be underestimated. All
life forms as we know are based on water, and all molecules
in living systems interact with it; thus water has likely driven
molecular evolution from the very beginning, here on earth
or plausibly elsewhere in the universe.
Perspective
In science, there are numerous examples of curiosity-driven
research and unintentional discoveries that led to technological breakthroughs and new economic development.
They include the mad pursuit of the DNA double helix
structure, DNARNA and RNARNA hybridizations, RNA
splicing, RNA as enzymes, telomeres, programmed cell
death, and the indispensible Worldwide Web. The discovery
of the lipid-like peptide is no exception. I started from asking
a question about the plausibly simplest enclosure that led to
pursue the lipid-like peptides. This unexpected curiositydriven question later led to the development of surfactants
for stabilizing diverse membrane proteins that will be important for design and fabrication of membrane-proteinbased molecular devices. Furthermore one of the lipid-like
Lipid-like Self-Assembling Peptides Zhang
peptides has been shown to effectively deliver siRNA to treat
naturally occurring breast cancers in dogs. Thus research
based on curiosity-driven questions must be strongly encouraged and supported despite the current emphasis on
application-driven research. The recent successful example
of a wide range of applications provides a glimpse of what is
coming for widespread uses of lipid-like peptides, from a
seemingly simple and curious question about the chemical
origin of life.
BIOGRAPHICAL INFORMATION
Shuguang Zhang earned his Ph.D. in Biochemistry & Molecular
Biology from University of California at Santa Barbara in 1988.
He published over 150 scientific papers in the areas from
designer self-assembling peptides to the study of membrane
proteins to emerging biosolar energy. He was an American
Cancer Society Postdoctoral Fellow and a Whitaker Foundation
Investigator at MIT. He is a distinguished Changjiang scholar in
China and a 2003 Fellow of Japan Society for Promotion of
Science. His work on designer peptide scaffolds won a 2004
R&D100 award. He was a 2006 John Simon Guggenheim Fellow
and a winner of the 2006 Wilhelm Exner Medal of Austria. He
was inducted as a foreign member of the Austrian Academy of
Science in 2010. He is also a Fellow of the American Institute of
Medical and Biological Engineering. He founded several biotech
startup companies using knowledge from curiosity-driven
research.
FOOTNOTES
*E-mail: [email protected].
The authors declare no competing financial interest.
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